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PurposePD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.Patients and methodsMGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).ResultsNo cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.ConclusionsPatients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.

Background Today, patients can access a myriad of information sources regarding plastic surgery procedures prior to meeting with a surgeon. Despite their widespread use, the role of these sources in a patient's decision-making remains undefined. We hypothesized that the physician remains the key information source for patients making surgical decisions in plastic surgery, but that other sources may deliver important insights and prove helpful to varying degrees. We also explored motivations for this outside information search and any differences in perceived value among patients. Methods We administered a survey regarding various information sources to our breast reconstruction, reduction, and abdominoplasty patients. Responses were compared between surgery groups and demographic groups. Ordinal logistic regression analysis was used to determine the impact of patient characteristics on helpfulness rank of different sources. Results Survey results were obtained from 58 patients, of whom 10 (17.2%) had abdominoplasty, 35 (60.3%) breast reconstruction, and 13 (22.4%) breast reduction. The most popular information sources prior to the first surgical appointment were Internet searches (56.9%) and family/friends/other patients (39.7%). After the initial appointment, the most useful sources were plastic surgeons (84.5%), and the Internet (36.2%). Most patients (73.5%) still sought outside information after their appointment. On a Likert-type scale of helpfulness, plastic surgeons ranked 4.28/5, followed by the web-based patient education platform, 3.73 and the Internet, 3.6. A total of 63% of participants listed plastic surgeons as their single most important source of information. In ordinal logistic regression analysis, non-white race was significantly associated with higher rank of surgeon helpfulness (p < 0.05). Relative to low-income patients, income $50-100k (p < 0.05) and $100k+ (p < 0.05) were associated with lower rank of surgeon helpfulness. Conclusions Most patients seek outside information prior to visiting with a surgeon from the Internet, social media, or family and friends. Patients consider plastic surgeons their most valuable information source overall, though still in need of supplementation for varying reasons. Additionally, certain demographic differences affect patient perception of information sources, and this is an important factor for surgeons to consider as they approach educating patients.

Background:Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to Propionibacterium acnes (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium. Objective:To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation. Furthermore, our study sought to investigate pathways by which lipids modulate immune responses in response to PA. Methods:Our studies focused on monocytes collected from human peripheral blood mononuclear cells, the monocytic cell line THP-1, and a lab strain of PA. Our studies involved the use of enzyme-linked immunosorbent, Western blot, reverse transcription polymerase chain reaction, small interfering RNA (siRNA), and microarray analysis of human acne lesions in the measurements of inflammatory markers. Results:G2A gene expression is higher in acne lesions compared to normal skin and is inducible by the acne therapeutic, 13-cis-retinoic acid. In vitro, PA induces both the Toll-like receptor 2-dependent expression of G2A as well as the production of the G2A ligand, 9-hydroxyoctadecadienoic acid, from human monocytes. G2A gene knockdown through siRNA enhances PA stimulation of interleukin (IL)-6, IL-8, and IL-1β possibly through increased activation of the ERK1/2 MAP kinase and nuclear factor kappa B p65 pathways. Conclusion:G2A may play a role in quelling inflammatory cytokine response to PA, revealing G2A as a potential attenuator of inflammatory response in a disease associated with a commensal bacterium.

This study aims to characterize the timeline and clinical features of onset, progression, and management of drug‐induced epidermal necrolysis in pediatric patients. Sixteen pediatric patients were retrospectively identified and selected if under age 18 years at admission with one identified culprit drug exposure. Culprit drugs were antiepileptics (12/16, 75%) and antibiotics (4/16, 25%). Notably, anti‐epileptic drugs (AED) had delayed onset and reported dose escalations that precipitated symptom onset; thus, patients prescribed AED with or without planned dose escalations should be monitored for prodromal symptoms longer than the typical onset window. [ABSTRACT FROM AUTHOR]

Circulating endothelial cell-derived microvesicles (EMVs) have been shown to be elevated with obesity and associated with endothelial dysfunction; however, their direct effect on endothelial cells is unknown. The experimental aim of this study was to determine the effect of EMVs isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production. EMVs (CD144þ microvesicles) were identified, enumerated, and isolated from plasma by flow cytometry from 24 sedentary adults: 12 normal-weight adults [8 M/4 F; age: 55 ± 6 yr; body mass index (BMI): 24.3 ± 0.7 kg/m²; EMV: 144 ± 53 EMVs/μL] and 12 adults with obesity (6 M/6 F; 59 ± 7 yr; BMI: 31.0 ± 1.1 kg/m²; EMV: 245 ± 89 EMVs/μL). Human umbilical vein endothelial cells were cultured and treated with EMVs from either normal-weight adults or adults with obesity. EMVs from obese adults induced significantly higher release of interleukin (IL)-6 (108.2 ± 7.7 vs. 90.9 ± 10.0 pg/mL) and IL-8 (75.4 ± 9.8 vs. 59.5 ± 11.5 pg/mL) from endothelial cells vs. EMVs from normal-weight adults, concordant with greater intracellular expression of phosphorylated NF-κB p65 (Ser536; active NF-κB) [145.0 ± 34.1 vs. 114.5 ± 30.4 arbitrary units (AU)]. Expression of phosphorylated p38-MAPK (15.4 ± 5.7 vs. 9.2 ± 2.5 AU) and active caspase-3 (168.2 ± 65.5 vs. 107.8 ± 40.5 AU), markers of cell apoptosis, was higher in cells treated with obesity-related EMVs. Phosphorylated endothelial nitric oxide synthase (eNOS) (Ser1177) expression (23.5 ± 7.2 vs. 34.7 ± 9.7 AU) and NO production (6.9 ± 1.4 vs. 8.7 ± 0.7 μol/L) were significantly lower in the cells treated with EMVs from obese adults. These data indicate that circulating EMVs from adults with obesity promote a proinflammatory, proapoptotic, and NOcompromised endothelial phenotype. Circulating EMVs are a potential mediator of obesity-related endothelial dysfunction. NEW & NOTEWORTHY: In the present study, we determined the effect of circulating endothelial cell-derived microvesicles (EMVs) isolated from adults with obesity on endothelial cell inflammation, apoptosis, and nitric oxide (NO) production in vitro. Circulating EMVs harvested from adults with obesity promoted a proinflammatory, proapoptotic, and NO-compromised endothelial phenotype. Elevated circulating EMVs in adults with obesity, independent of other cardiometabolic risk factors, are a potential novel systemic mediator of obesity-related endothelial dysfunction and vascular risk. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. The factors that initiate, promote, and accelerate vascular diseases and events in SCI are poorly understood. Clinical interest in circulating endothelial cell-derived microvesicles (EMVs) and their microRNA (miRNA) cargo has intensified due to their involvement in endothelial dysfunction, atherosclerosis, and cerebrovascular events. The aim of this study was to determine whether a subset of vascular-related miRNAs is differentially expressed in EMVs isolated from adults with SCI. We assessed eight adults with tetraplegia (7 male/1 female; age: 46±4 years; time since injury: 26±5 years) and eight uninjured (6 male/2 female; age: 39±3 years). Circulating EMVs were isolated, enumerated, and collected from plasma by flow cytometry. The expression of vascular-related miRNAs in EMVs was assessed by RT-PCR. Circulating EMV levels were significantly higher (~130%) in adults with SCI compared with uninjured adults. The expression profile of miRNAs in EMVs from adults with SCI were significantly different than uninjured adults and were pathologic in nature. Expression of miR-126, miR-132, and miR-Let-7a were lower (~100–150%; p <.05), whereas miR-30a, miR-145, miR-155, and miR-216 were higher (~125–450%; p <.05) in EMVs from adults with SCI. This study is the first examination of EMV miRNA cargo in adults with SCI. The cargo signature of vascular-related miRNAs studied reflects a pathogenic EMV phenotype prone to induce inflammation, atherosclerosis, and vascular dysfunction. EMVs and their miRNA cargo represent a novel biomarker of vascular risk and a potential target for intervention to alleviate vascular-related disease after SCI. [ABSTRACT FROM AUTHOR]